Induction of Caspase-11 by Aspartyl Proteinases of Candida albicans and Implication in Promoting Inflammatory Response

Abstract

We recently demonstrated that the secreted aspartyl proteinases (Saps), Sap2 and Sap6, of Candida albicans have the potential to induce the canonical activation of the NLRP3 inflammasome, leading to the secretion of interleukin-1␤ (IL-1␤) and IL-18 via caspase-1 activation. We also observed that the activation of caspase-1 is partially independent from the NLRP3 activation pathway. In this study, we examined whether Sap2 and Sap6 are also able to activate the noncanonical inflammasome pathway in murine macrophages. Our data show that both Sap2 and Sap6 can activate caspase-11 through type I interferon (IFN) production. Caspase-11 cooperates to activate caspase-1, with a subsequent increase of IL-1␤ secretion. Endocytosis and internalization of Saps are required for the induction of type I IFN production, which is essential for induction of noncanonical inflammasome activation. Our study indicates a sophisticated interplay between caspase-1 and caspase-11 that connects the canonical and noncanonical pathways of inflammasome activation in response to C. albicans Saps.O nly a few Candida species are known as normally harmless commensals in the gastrointestinal, genitourinary, or oropharyngeal tract of most healthy individuals, but these can also cause superficial or systemic infections (1, 2). In fact, Candida species are the fourth most common cause of hospital-acquired systemic infections associated with a mortality rate of up to 50% (3). The leading Candida species, which causes more than 50% of all cases of candidiasis, is Candida albicans.C. albicans is equipped with an arsenal of fitness and virulence attributes which are crucial for causing infections (4). Morphological plasticity is key to the shift of C. albicans from commensalism to pathogenicity and includes the yeast-to-hypha transition and the production of pseudohyphae (filamentous forms). While pseudohyphae consist of elongated ellipsoidal cells with constrictions at the septa, true hyphae lack constrictions at the septa and express a distinct set of hypha-associated genes (5, 6). Other morphologies include white/opaque switching and chlamydospores (4).This morphological flexibility greatly contributes to the pathogenesis of candidiasis, and the different morphological forms are believed to play different roles at the various stages of infection, including recognition by immune cells, adherence to mucosal surfaces, invasion and tissue damage, and escape from immune system surveillance (7,8). Additional important virulence factors produced by C. albicans are the secreted aspartyl proteinases (Saps). These enzymes are encoded by a family of 10 SAP genes that have been extensively studied as key virulence determinants of C. albicans (1). Of note, Sap2 is the most abundant protease expressed by yeast cells in medium with protein as the sole source of nitrogen; expression of Sap1 and Sap3 has been associated with white/opaque switching, while Sap4 to Sap6 are hypha specific (1). Similar proteases are produced by other pathogenic Candida species, including...

Aspartyl Proteinases of Eukaryotic Microbial Pathogens: From Eating to Heating

“…In mouse models of vaginal infection, some Saps (mostly Sap2 and Sap6, or Sap5, depending on the model [33,39]), appear to be responsible for the expression of key immunopathogenic markers of landmark inflammatory events. This includes polymorphonuclear (PMN) cell infiltration and production of pro-inflammatory cytokines, such as IL-1β and IL-18, via the activation of inflammasome-mediated caspase-1 and possibly other caspases [41]. The use of individual or collective subfamily SAP knockout strains, human anti-Sap Fragment antigen binding (Fab), and whole transcriptome analyses has shown that inflammation in vaginal disease can be dampened either downstream, by pharmacological inhibition of NLRP3 inflammasome and blockade of IL-1β receptor, or upstream, by specifically affecting Sap production or activity by anti-Sap antibodies or pepstatin A, without affecting the infectious fungus burden [38,39] (Fig 3).…”

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

“…Candida albicans is a pathogenic yeast that induces candidiasis and secretes aspartyl proteinases, which are the key determinants for its pathogenesis. Of the several types of secreted aspartyl proteinases, secreted aspartyl proteinase 2 and secreted aspartyl proteinase 6 were reported to play a critical role in the activation of the caspase-11 non-canonical inflammasome i.e., they induced the activation of caspase-11 non-canonical inflammasome in macrophages in a type I IFN-dependent manner [28]. This study provides the insight that not only Gram-negative bacteria, but also yeast can activate the caspase-11 non-canonical inflammasome in the inflammatory responses.…”

Saccharomyces cerevisiae-Based Probiotics as Novel Antimicrobial Agents to Prevent and Treat Vaginal Infections

“…However, only the live and not the attenuated yeast strongly suppressed some of the crucial virulence factors of C. albicans, such as its capacity to switch from the yeast to the hyphal form and the ability to express aspartyl proteases Gabrielli et al, 2018). These effects were related to the ability of the live yeast to significantly inhibit the expression of two important hyphal growth-associated genes, in particular the hyphal wall protein 1 (HWP1) and extent of cell elongation 1 (ECE1), as well as the expression of two secretory aspartyl proteinases (SAPs), SAP2, and SAP6, which play a key role in the immunopathogenesis of vaginal candidiasis (Naglik et al, 2003;Cassone and Cauda, 2012;Gabrielli et al, 2015;Pericolini et al, 2015;Roselletti et al, 2017). The suppression of SAP2 and SAP6 gene expression mirrored the reduction of the inflammatory process associated with the pathogenesis of Candida vaginitis .…”